BRI Cancer Research Center

Focus

Dr. David Kwiatkowski is an acknowledged expert on tuberous sclerosis (TS), a rare genetic disorder in which multiple tumors develop in different parts of the body of affected individuals. TS occurs in about 1 in 6000 live births. Patients with this condition suffer from benign tumors in many different organs, including brain, kidney, lung, and skin. Although the tumors caused by TS are benign (they do not directly invade adjacent tissues), they are clinically relevant because of their tendency to grow in important organs. Clinically significant consequences of TS include kidney failure, the progressive lung disease lymphangioleiomyomatosis (LAM), several types of brain tumors, seizures, and autism.

Background

A graduate of the California Institute of Technology with a concentration in mathematics, Dr. Kwiatkowski received his Ph.D. from the Massachusetts Institute of Technology (MIT) and his M.D. from Columbia University's College of Physicians and Surgeons. He did his postgraduate training at the Massachusetts General Hospital (MGH), and after his residency, fulfilled a postdoctoral fellowship in hematology-oncology, at which time he began to develop an interest in TS. Recruited to the Brigham in 1991 by Tom Stossel, Chief of the Division of Hematology, Dr. Kwiatkowski also became the Director of the Genotyping Facility of the Harvard-Partners Center for Genetics and Genomics. He is now a professor of medicine, a new member of the Division of Translational Medicine, and an active member of the Brigham Thoracic Oncology Program.

Research

The linchpin of Dr. Kwiatkowski’s research was the discovery of two genes (TSC1 and TSC2) that cause TS when mutated. This groundbreaking work was published in the journal Science in 1997. Many other laboratories began to contribute to this body of work, and we now know that the TSC1 and TSC2 genes regulate the activation of a critical enzyme, called mTOR, which acts in a signaling pathway that controls cell growth. This critical pathogenic insight led to the discovery of a new use for an old drug, Rapamycin (sirolimus), which works to block mTOR (mammalian Target Of Rapamycin). A series of Phase I Clinical Trials have shown great promise for treating patients with TS. Dr. Kwiatkowski says, “It has been very exciting for both the research community and the patients who have this condition. Before this drug, there were no treatments other than surgical approaches or therapies that were tangential to the problem. Now we can give a therapy that is directed at the molecular basis of the disease.” Of further note, scientists have also learned that the mTOR pathway contributes to the growth of many different kinds of cancer, in addition to the tumors that are seen in TS. Thus, lessons learned from TS have had broad basic and applied implications for other cancer research.

Laboratory

Dr. Kwiatkowski’s laboratory is supported by a fluid workforce of a dozen or more scientific researchers, many of whom move on to other established cancer centers after several years of training and research. Current members include Dr. David Miller, Genetics Instructor at Children’s Hospital, Po-Shun Lee, a staff Pulmonologist in the Department of Pulmonary Medicine at Brigham and Women’s Hospital, and two fellows.

Funding

Dr. Kwiatkowski’s laboratory derives the bulk of its support from the National Institutes of Health and National Cancer Institute. 

Collaborations

“Recruiting, developing, fostering, and mentoring associates” is a central feature of the laboratory, relates Dr. Kwiatkowski. “Nobody does this alone.” Having “high quality people come into your lab who are happy about the work they do, engaged, and focused is critical.” When asked whether the level of training and experience were also key factors, Dr. Kwiatkowski agreed that “postdoctoral fellows tend to be the most productive. They have already had significant research training and are able to take the project and move forward with it with less direction." “But, you know,” he ventured, “I think interest and drive on the part of the person who comes to the lab is actually the most important thing. If they’ve got that, they’ll learn what it takes to get things done.”

Importance of Being at the Brigham

Dr. Kwiatkowski describes the atmosphere at Brigham and Women’s Hospital as highly conducive for making significant scientific breakthroughs. “For many years,” he states, “the Brigham has recognized, perhaps better than any other institution in the country and even the world, the importance of biomedical research.” In fact,” he adds, “support from one’s department chair, colleagues, and institution is probably the single most important aspect of developing one’s career and pursuing scientific discovery.”

In speaking about the nature of scientific discovery and importance of perseverance, Dr. Kwiatkowski shares his favorite story about renowned surgeon and cancer scientist, Dr. Judah Folkman, best known for his work on tumor angiogenesis. He recounts, “After delivering a lecture to medical students, Dr. Folkman was prompted for his personal view on the scientific process. Dr. Folkman replied, ‘It’s like night driving. You’ve got headlights on in front of you, you can see something out there, but there’s a lot of darkness all over the place, and you don’t know exactly where you’re going.’ ”

Selected References

van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowski J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277:805-808.

Manning BD, Logsdon MN, Lipovsky AI, Abbott D, Kwiatkowski DJ, Cantley LC. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev 2005;19:1773-1778.

Kozlowski P, Roberts P, Dabora S, Franz D, Bissler J, Northrup H, Au KS, Lazarus R, Domanska-Pakiela D, Kotulska K, Jozwiak S, Kwiatkowski DJ. Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Human Genet 2007;121:391-400.

This page was last modified on 7/7/2007